Overall Program Summary The overall goal of this program is to improve outcomes in the treatment of human leukemias with more effective and less toxic therapies. We have made significant progress during the previous funding period in understanding the genetic basis of acute myeloid leukemia (AML), developing more effective treatments for human leukemias, and validating predictors of therapeutic response. Pre-clinical and clinical studies from Drs. Griffin and Stone, funded by this P01, contributed directly to the FDA-approval of midostaurin for FLT3-mutant AML during the last funding period. Work from Dr. Letai, funded by this P01, contributed directly to FDA- approval of venetoclax for AML during the last funding period, to the demonstration that apoptotic priming predicts response to therapy in leukemia. Work from Dr. Ebert, funded by this P01, elucidated the mechanism of action of lenalidomide and its analogs, leading to widespread drug development in academia and the private sector focused on protein degradation. And work from Dr. Armstrong, funded by this P01, led to a clinical trial of a DOT1L inhibitor with evidence of response in AML. In this renewal, we propose studies to continue this record of therapeutic development for leukemia, leveraging a sample bank, a clinical and genetic database, a xenograft bank, and a team of laboratory and clinical investigators with a long and successful track record of collaborative research. Specifically, we will investigate apoptotic priming and prediction of response to targeted AML therapies in Project 1 (Dr. Letai); the targeting of CBL-mediated signaling and ubiquitin ligase activity in Project 2 (Dr. Ebert); the modulation of the SALL4B transcription factor in Project 3 (Drs. Tenen, Chai, and Qi); and the biology and therapeutic targeting of zinc finger transcription factors in Project 4 (Drs. Armstrong and Fischer). Projects 2, 3, and 4 all focus on the modulation of ubiquitin ligase activity to develop candidate therapeutics (Projects 3 and 4) or understand leukemia biology (Project 2). The team will use a common set of drugs, assays, and model systems. All projects will characterize mutations in primary samples using the Rapid Heme Panel, will test molecules in vitro using dynamic BH3 profiling with Dr. Letai (Project 1), and will use a common set of xenografts. All projects will interact with Drs. Stone and Deangelo, leading leukemia clinical investigators, to move candidate therapeutics into high impact clinical trials with deep correlative studies. In aggregate, these studies will provide insights into leukemia biology, develop highly novel therapeutic strategies, and lead to the advancements in the treatment of AML.